Bupropion is known as an antidepressant of the aminoketone class, chemically unrelated to tricyclics, tetracyclics, selective serotonin re-uptake inhibitors (SSRIs), or other known antidepressant agents. The drug resembles a psycho-stimulant in terms of its neurochemical and behavioral profiles in-vivo, but it does not reliably produce stimulant-like effects in humans at clinically prescribed doses. Its structure closely resembles that of diethylpropion and it is related to phenylethylamines. It is designated as (±)-1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1-propanone hydrochloride and by its generic name amfebutamone hydrochloride. Bupropion hydrochloride is commercially available as an immediate release form (WELLBUTRIN®), a sustained release form (WELLBUTRIN® SR and ZYBAN®), and an extended release form ((WELLBUTRIN® XL). Both WELLBUTRIN® SR and ZYBAN® are chemically and pharmaceutically identical.
The neurochemical mechanism of the antidepressant effect of bupropion is not well known. Bupropion affects chemicals within the brain that nerves use to send messages to each other. These chemical messengers are called neurotransmitters. The neurotransmitters that are released by nerves are taken up again by the nerves that release them for reuse (this is referred to as reuptake). Many skilled artisans believe that depression is caused by an imbalance among the amounts of neurotransmitters that are released. Bupropion is a selective catecholamine (dopamine and norepinephrine) reuptake inhibitor, and works by inhibiting the reuptake of the neurotransmitters dopamine and norepinephrine, an action which results in more dopamine and norepinephrine made available to transmit messages to other nerves. It has a small effect, if any, on the serotonin reuptake mechanism. Accordingly, bupropion is unique in that its major effect is on dopamine, an effect which is not shared by the SSRIs, e.g. paroxetine (PAXIL®), fluoxetine (PROZAC®), sertraline (ZOLOFT®) or the tricyclic antidepressants or TCAs, e.g. amitriptyline (ELAVIL®), imipramine (TOFRANIL®), desipramine (NORPRAMIN®).
Bupropion can also be used to treat other conditions, non-limiting examples of which include nicotine addition (e.g. smoking cessation), weight gain (e.g. obesity), Parkinson's disease, and seasonal affective disorder. WELLBUTRIN®, WELLBUTRIN® SR and WELLBUTRIN® XL are used clinically for the management of major depressive disorder, bipolar depression mood disorder, other mood disorder, anxiety disorders, generalized anxiety disorder, panic disorder, post-traumatic stress disorder, and seasonal affective disorders, and have been approved for use in the treatment of major depressive disorder. ZYBAN® has been approved as an aid to patients wanting to quit smoking. WELLBUTRIN®, the immediate release formulation of bupropion, is dosed three times a day, suitably with 6 or more hours in between doses. For patients requiring more than 300 mg bupropion a day, each dose is prescribed not to exceed 150 mg. This requires administration of the tablets at least 4 times a day with at least 4 hours in between doses. The immediate release formulation results in more than a 75% release of the bupropion into the dissolution media in 45 minutes. The sustained release products are dosed twice daily, and the extended release products are dosed once daily.
Certain advantages exist in using bupropion for the treatment of diseases and conditions. For example, bupropion does not inhibit monoamine oxidase, and does not significantly block the reuptake of serotonin, unlike other neuronal monoamine reuptake inhibitors. Administration of bupropion can thus avoid or lessen many adverse effects commonly associated with other antidepressants such as tricyclic agents and monoamine oxidase inhibitors.
One of the known major side effects of bupropion is the incidence of seizures (e.g. grand-mal epileptic seizures), which is known to be strongly associated with the dose strength of the bupropion. For example, with WELLBUTRIN® at the originally recommended dosage (400-600 mg) the incidence of seizures in those treated with the drug was found to be significantly greater than other antidepressants, and so in 1986 the drug was removed from the market. It was shown that the risk of seizures increased significantly between the 450 mg/day dosage and the 600 mg/day dosage. As a result, bupropion was re-introduced into the market in 1989 with the maximum dose of 450 mg/day. However, it has been documented that seizures occur in patients taking bupropion not only in overdose but also in doses considered to be therapeutic (i.e. 450 mg/day or less) [Pesola & Avasarala, Bupropion seizures proportion among new-onset generalized seizures and drug related seizures presenting to an emergency department, J. Emerg. Med. 2002, 22, 235-239.] The high concentrations of bupropion needed for efficacy (e.g. antidepressant efficacy) establish a high floor concentration, and thus sets the stage for a narrow therapeutic index, in light of its concentration-dependent risk of causing seizures. [Preskorn S., Bupropion: What Mechanism of Action? J. Practical Psychiatry and Behavioral Health, January 2000, 272-276.]
Bupropion is known to lower the seizure threshold, and has been cited as one of the leading causes of drug related seizures [third behind cocaine intoxication and benzodiazepine withdrawal seizures—Davidson J., Seizures and Bupropion: A Review, J. Clin. Psychiatry, 1989, 50, 256-61.]. Bupropion alone or in combination with other medications, is known to induce seizures in some patients with no prior record of seizure activity. It is not uncommon for patients to receive treatment with other antidepressant and/or atypical antipsychotic medications in combination with bupropion. As such, there is a need to manage, reduce, or eliminate the incidences of seizures resulting from bupropion administration, whether administered alone or in combination with other medications prone to lower the seizure threshold. Bupropion has also been known to produce seizures in combination with non-prescription (recreational) drugs such as cocaine and alcohol.
The selection of a suitable salt for a drug candidate is recognized as an important step in the preclinical phase of drug development. Changing the salt form of a drug is a recognized means of modifying its chemical and biological properties without modifying its structure. The choice of a particular salt form can have a profound effect on the physicochemical properties of the drug (e.g. dissolution rate, solubility, stability, and hygroscopicity). Substitution of one salt form of a drug for another can alter therapeutic efficacy, safety and/or quality, which are critical for the optimal formulation of the dosage form and large-scale manufacturing. However, as yet there is no reliable way of predicting exactly what effect changing the salt form of an active drug will have on its biological activity. Furthermore, even after many salts of the same basic agent have been prepared, no efficient screening techniques exist to facilitate selection of the salt most likely to exhibit the desired pharmacokinetic, solubility, and formulation profiles. In short, there is no known reliable way of predicting the influence of a particular salt species on the behavior of the parent compound in dosage forms. [Berge et al., Pharmaceutical Salts, Journal Pharm. Sci., 1977, Vol. 66, No. 1; Verbeeck et al. Generic substitution: The use of medicinal products containing different salts and implications for safety and efficacy, EP Journal Pharm. Sci, 28, 2006, 1-6.] A decision to change the salt form at a later stage introduces the need to repeat toxicological, formulation and stability tests, with obvious implications for the overall development and production time for the new pharmaceutical product.
According to the CAS® (“Chemical Abstracts Registry”) Database, as of the date of this application, the only other salts of bupropion that have been previously reported are the hydrochloride (HCl), (2Z)-2-butenedioate, (2E)-2-butenedioate, methane sulfonate, formic acid, 2-hydroxy-1,2,3-propanetricarboxylate, phosphate and trifluoromethanesulfonate salts.
Sodium bromide and potassium bromide are salts that have been widely used as an anticonvulsant and a sedative in the late 19th and early 20th centuries. Its action is due to the bromide ion. As of the date of this application, bromide has not been approved by the US Food and Drug Administration (FDA) for use in humans to control seizures. However, in Germany it continues to be approved for use as an antiepileptic drug for humans, particularly children and adolescents (sold under the brand name DIBRO-BE MONO®). The indications include severe forms of generalized tonic-clonic seizures, early-childhood-related Grand-Mal-seizures, and also severe myoclonic seizures during childhood. One tablet contains a therapeutic dose of 850 mg of potassium bromide. Bromide was the first drug found to be effective for the treatment of epilepsy in humans. Bromide has also been used as a veterinary drug, e.g. as an antiepileptic medication for dogs and cats.
Recommended therapeutic dose levels of bromide for treating epilepsy have been reported. For adults, a reported usual dose ranges from 3-6 grams/day [Niedermeyer E., ed. Benzodiazepines and other antiepileptic drugs, In: The epilepsies: Diagnosis and management, Baltimore: Urban & Schwarzenberg, 1990, 311-2; Ryan and Baumann; Bromides in Epilepsy Treatment, Pediatr Neurol, 1999, 21; 523-528.]. For children under 6 years of age, dose levels of 600-1800 mg/day have been recommended in two to three doses. For children over 6 years of age, it has been recommended that 300 mg to 1 gram be given three times daily. [Dreifuss F. E. and Bertram D. H., Bromide therapy for intractable seizures, Epilepsia, 1986, 27; 593; Ryan and Baumann; Bromides in Epilepsy Treatment, Pediatr Neruol, 1999, 21; 523-528.]. The ED50 (minimum effective dose required to produce a desired effect in 50% of test population) for sodium bromide against chemically-induced seizures (induced by pentylenetetrazole) in mice has been reported to be 910 mg/kg [J. S. Grewal et al., Journal of Pharmacology and Expt'l Therapeutics, 1954, Vol. 112, Issue 1, 109-115.]
Bromide was the principal anticonvulsant of choice until the introduction of Phenobarbital in 1912 and other safer anticonvulsants. It was subsequently discovered that the known therapeutic dose levels of bromide induced bromism and a number of other significant toxic effects. The known therapeutic index is very small for bromide. As with other anticonvulsants, sometimes even therapeutic doses give rise to intoxication. Often indistinguishable from ‘expected’ side-effects, these toxic effects can include: bromism (i.e. central nervous system reactions reaching from somnolence to coma, cachexia, exicosis, loss of reflexes or pathologic reflexes, clonic seizures, tremor, ataxia, loss of neural sensitivity, paresis, papillar edema of the eyes, abnormal speech, cerebral edema, frank delirium, aggressivity, psychoses); loss of appetite; nausea/emesis; lethargy; propensity to sleep during the daytime; depression; loss of concentration and memory; confusion; headache; and skin diseases such as acne-form dermatitis.
Bromide's precise mechanism of action is unknown. The pharmacological mechanism of bupropion-induced seizures and the usefulness of antiepileptic drugs (e.g. bromide) in treating such seizures have not been established. There is limited knowledge about the effectiveness of antiepileptic drugs in bupropion-induced seizures in mice [P. Tutka et al., Epilepsy Research 64, 2005, 13-22.], and nothing is known about the effectiveness of bromide in controlling bupropion-induced seizures. While no formal studies have been carried out to determine the therapeutic dose ranges for the effectiveness of bromide against bupropion-induced seizures, the therapeutic dose ranges for the effectiveness of bromide against other known seizures are known. For example, the therapeutic dose level for bromide against pentylenetetrazole-induced seizures is known to be 910 mg/kg [M. S. Grewal et al., Journal of Pharmacology And Experimental Therapeutics, Vol. 112, Issue 1, 109-115, 1954]. For a number of other anti-epileptic drugs (e.g. clonazepam, vigabatrin, etosuximide, valproate), the therapeutic dose levels that are required for the treatment of bupropion-induced seizures are comparable to the dose levels that are required for the treatment of pentylenetetrazole-induced seizures in mice. [P. Tutka et al. Epilepsy Research 64 (2005) 13-22; J. J. Luszczki, 2005, 30, 958-973; J. A. Armijo et al. Pharmacological Res. 2005, 51, 489-496; K. K. Borowicz et al. Epilepsia, 2004, 45(10), 1176-1183; S. J. Czuczwar et al., Polish Journal of Pharmacology, 2003, 55, 363-370; P. Tutka et al., J. Neural Transmission, 2002, 109, 455-466; K. K. Borowicz et al. European Neuropsychopharmacology 2004, 14, 77-85; and K. K. Borowicz et al., Polish Journal of Pharmacology, 2004, 56, 187-193.]
There remains a need for a bupropion composition that can be used for the treatment and/or prevention of a condition (e.g. major depressive disorder and nicotine addiction) in subjects that can benefit from bupropion administration, and that can provide fewer incidences of and/or reduce the severity of seizures associated with the administration of bupropion, as compared to known bupropion compositions.
The development of a stable, once daily modified-release bupropion formulation comprising safe levels of the bupropion hydrobromide salt; that provides for the reduction of incidences and/or reduction of the severity of bupropion-induced seizures as compared to an otherwise similar or identical composition containing an equivalent molar amount of bupropion hydrochloride; would be an advance in the art.